Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Patent
1995-05-30
1998-03-31
Kight, John
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
562400, 540 1, 424 111, 424 165, 534 10, A61K 4900, G01N 3100, G01N 3348
Patent
active
057335281
DESCRIPTION:
BRIEF SUMMARY
This invention refers to new compounds endowed with a chelating property for paramagnetic bi- and trivalent metal ions, their chelates with said metal ions and their use as contrast agents in magnetic resonance imaging (MRI).
The use in medicine of a high number of these complexes is widely reported: for instance as stabilizers for the pharmaceutical preparations or antidotes in case of ingestion of toxic metal species.
Physiologically tolerable complexes formed by chelating agents and bi- or trivalent metal ions are used as diagnostic agents in imaging techniques such as X-ray, nuclear magnetic resonance (NMR) and scintigraphy.
In particular, magnetic resonance imaging (MRI) is a renowned powerful diagnostic procedure used in medical practice (see Stark, D. D., Bradley, W. G., Jr., Eds. "Magnetic Resonance Imaging" The C. V. Mosby Company, St. Louis, Mo. (USA), 1988) which relies on the use of paramagnetic pharmaceutical compositions, preferably containing chelated complexes of bi- or trivalent paramagnetic metal ions, usually belonging to the class of transition metals, or rare earth, with polyaminocarboxylic acids and/or their derivatives or analogues.
The images (basically coming from the NMR signal of water protons) are the result of a complex interaction of different parameters, such as proton density and T.sub.1 and T.sub.2 relaxation times. A contrast enhancement can be obtained through the administration of exogenous chemical substances which significantly change the resonance properties of nearby water protons (see Lauffer, R. B. Chem. Rev. 1987,87,901). Due to the high capacity of gadolinium complexes of reducing the relaxation times of hydrogen nuclei of nearby water molecules through dipolar interaction, scientists have investigated, patented and published a lot of works on these complexes. And some of them have been approved as MRI contrast media (Gd-DTPA/Dimeg, N-methylglucamine salt of gadolinium diethylenetriaminepentaacetic acid, MAGNEVIST.RTM., Schering; Gd-DOTA/Dimeg, N-methylglucamine salt of gadolinium 1,4,7,10-tetraazacyclo dodecan-1,4,7,10-tetracetic acid, DOTAREM.RTM., Guerbet).
A list of significant patent documents showing the state of the art in this diagnostic field, even though uncompleted, is represented by: EP 71564 (Schering), U.S. Pat. No. 4,639,365 (Sherry), U.S. Pat. No. 4,615,879 (Runge), DE-A-3401052 (Schering), EP 130934 (Schering), EP 65728 (Nycomed), EP 230893 (Bracco), U.S. Pat. No. 4,826,673 (Mallinckrodt), U.S. Pat. No. 4,639,365 (Sherry), EP 299795 (Nycomed), EP 258616 (Salutar), WO 8905802 (Bracco).
The choice of the suitable compound is based the evaluation of different parameters such as relaxivity, toxicity, distribution in the human body, excretion and so on. Three important properties are needed to use a complex of Gd.sup.(3+) as a potential MRI contrast agent. Firstly, a high thermodynamic stability (and possibly kinetic), that's to say a low tendency to release free Gd.sup.(3+) ions, highly toxic in vivo. Secondly, the presence of at least one water molecule directly coordinated to the metal in the inner coordination sphere and able to rapidly exchange with the bulk one. Thirdly, a high water solubility (.gtoreq.0.5 mol/L). Although Gd-DTPA and Gd-DOTA are stable and water-soluble gadolinium chelates, they are ionic compounds (that's to say formally charged, in fact Gd-DTPA is equal to -2, while Gd-DOTA is -1) which are made neutral with the formation of N-methylglucamine salts. Therefore the solutions contain charged particles, which affect their osmolality characteristics. Injectable concentrated solutions (0.5-1.9M) of such salts are much more hyperesmoiai compared to blood and physiological fluids. Hyperosmoiality can produce, in vivo, oedemas and other undesired side effects.
As a consequence, several attempts have been made to develop new non-ionic metal complexes, which solve or limit the above mentioned drawbacks. A solution was proposed by Tweedle M. F. et al. in U.S. Pat. No. 4,885,363 which deals with the preparation of gadolinium complex with
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Anelli Pier Lucio
Beltrami Andrea
Felder Ernst
Lolli Marco
Virtuani Mario
Dibra S.p.A.
Jones Dameron
Kight John
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